Frequency, Predictors, and Economic Impact of Upward Dose Adjustment of Infliximab in Managed Care Patients With Rheumatoid Arthritis

OBJECTIVES: To examine dosing patterns and costs among rheumatoid arthritis (RA) patients newly treated with infliximab in a large national health care claims database. METHODS: Using data from a proprietary database of pharmacy and medical claims for 75 U.S. health plans, RA patients newly treated with infliximab between June 2000 and June 2002 were selected and assigned an index date based on the first infusion. A pretreatment period of 6 months was created; patients were also followed for a minimum of 6 months after the initial infusion. Follow-up was allowed to vary beyond this minimum 6 months in order to preserve all available patient data. A maintenance number of infliximab vials was determined as of the second infusion; patients with ³1 subsequent increase in vials used or ³2 intervals between infusions of less than 49 days were considered to have had an upward dose adjustment. Differences (i.e., between those with upward dose adjustment and those with no upward dose) in patient characteristics were examined using descriptive statistics. In addition, time to upward dose adjustment and factors influencing its likelihood were analyzed using Kaplan-Meier and Cox proportional hazards techniques. Finally, differences in RA-related and unrelated costs (medication, outpatient, inpatient, and total, expressed in 2003 dollars) were examined using Wilcoxon rank-sum tests and were also stratified by a number of patient characteristics found to differ between the 2 groups. RESULTS: A total of 1,236 patients met all study entry criteria and were included in these analyses. One or more upward dose adjustments were experienced by 61.7% (N=762) of patients during an average of 15 months of follow-up (median=13 months, range=6 to 31 months). The majority (63.3%) of upward dose adjustments were due to increases in the number of billed vials. Median time to upward dose adjustment was 254 days and declined steadily based on year of initiation (from 330 days in 2000 to 224 days in 2002). Factors significantly influencing upward dose adjustment included pretreatment use of leflunomide, comorbid Crohn's disease, and pretreatment liver function testing. During followup, patients in the upward dose adjustment group used a mean (SD) of 30.28 (20.90) vials of infliximab, compared with 15.90 (14.28) among those not adjusting dose (P less than 0.001). Annualized (i.e., standardized to a 365-day rate) RA-related costs were higher by more than 50% among patients with upward dose adjustment (SD $22,283 [$20,517] versus $14,425 [$10,828] for those without upward dose adjustment; P less than 0.001); differences were driven almost entirely by the costs of infliximab itself ($16,336 [$9,490] versus $9,573 [$6,790], P less than 0.001). CONCLUSIONS: In a cohort of managed care members with RA, upward dose adjustment with infliximab was frequent and appeared to occur earlier in the drug therapy in 2002 compared with 2000. Upward dose adjustment was associated with significant increases in drug treatment costs; therefore, payers and providers should consider the impact of current dosing trends when monitoring the use of biologics for autoimmune diseases.

dysfunction. Though the clinical hallmark of the disease is joint inflammation (usually in a symmetric fashion affecting both large and small joints), extrarticular manifestations include constitutional features such as fever and weight loss as well as pleural effusions, pericarditis, scleritis, and vasculitis. Epidemiological studies have shown that the life expectancy of patients with RA is reduced by between 3 and 18 years. 3 Risk factors associated with a poor prognosis include a polyarticular presentation, high levels of rheumatoid factor (the serological marker of RA, seen in more than 80% of patients), positive family history, tobacco use, and lack of formal education.
The goals of therapy are to relieve pain and to prevent joint destruction and disability. Prior to the advent of biological therapies that are directed at specific targets involved in the inflammatory process underlying RA, the pharmacologic treatments commonly used included nonsteroidal antiinflammatory agents (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs) that nonspecifically abrogated synovial inflammation. These DMARDs included injectable gold salts, sulfasalazine, methotrexate, and leflunomide. The 2002 American College of Rheumatology (ACR) guidelines for the treatment of RA recommend that all patients with RA receive DMARD therapy within 3 months of diagnosis. 4 Methotrexate remains the most commonly used DMARD (alone and in combination with other DMARDs) and results in clinically meaningful improvements for the majority of patients with RA, but its use is limited by its ineffectiveness in more than 25% of patients and drug-induced toxicities (e.g., nausea, mouth ulcers, diarrhea). In addition, methotrexate has not been shown to independently halt radiographic progression of disease, heal erosions, or induce disease remission.
Over the last 20 years, several insights have been made regarding the immunological processes involved in the pathogenesis of RA. Proinflammatory cytokines (tumor necrosis factoralpha [TNF-α], interleukin-1) produced by macrophages within diseased synovium help establish a self-perpetuating cycle of inflammatory mediators of cartilage destruction. Elevated levels of TNF-α and interleukin-1 were noted in the serum and synovial fluid of RA patients. Advances in biotechnology have led to the development of inhibitors of TNF-α that in randomized, double-blind, controlled trials have been shown to significantly mitigate the clinical and radiographic manifestations of RA and offer RA patients additional options for the treatment of refractory disease. All of the TNF-α blockers have been associated with significantly higher ACR 50 and 70 (50% and 70% improvement in disease manifestations, respectively) responses than methotrexate, considered to be the "gold standard" DMARD.
Etanercept (Enbrel), approved by the U.S. Food and Drug Administration (FDA) for the treatment of RA in November 1998, is a soluble receptor of TNF-α formed by the fusion of 2 naturally occurring soluble human 75-kilodalton TNF receptors linked to an Fc (perfluoro-compound) portion of an Ig-G1 (GI isotope of human immunoglobulin) and is given by subcutaneous injection either twice weekly (25 mg) or once weekly (50 mg). Higher dosages and more frequent administration of etanercept have not been found to be clinically effective. Etanercept can be given alone or in combination with other DMARDs, most commonly methotrexate. Recent data from controlled clinical trials have shown that the combination of etanercept and methotrexate results in significantly better radiographic outcomes than when either agent is used alone. 5 Side effects include local injection reactions (usually of no clinical consequence), susceptibility to infection, and, rarely, demyelinating neuropathies that are usually reversible upon discontinuation of the drug. Etanercept' s half-life is 70 hours, the shortest of the currently available TNF-α inhibitors.
Infliximab (Remicade), a chimeric monoclonal antibody directed against TNF-α, is given by intravenous infusion in an office or clinic setting and is approved for use only with methotrexate. It was first approved by the FDA for the treatment of Crohn' s disease in August 1998 (approval for induction and maintenance of Crohn' s remission followed in July 2002) and was approved by the FDA for RA in November 1999 and for ankylosing spondylitis in December 2004. Patients are initially infused with infliximab at a dose of 3 mg/kg at 0 weeks, followed by repeat infusions at 2 and 6 weeks and then every 8 weeks thereafter. Product labeling requires concurrent use with methotrexate, and "for patients who have an incomplete response, consider adjusting the dose up to 10 mg/kg or treating as often as every 4 weeks." 6 Like etanercept, infliximab has also been shown to slow radiographic progression of disease. 7 In addition to the side effects seen with etanercept, infliximab has been associated with infusion-related reactions and reactivation of latent tuberculosis. The half-life of infliximab is between 8 and 9.5 days.
Adalimumab (Humira), approved by the FDA in December 2002, is a fully human monoclonal antibody directed against TNF-α and given by subcutaneous injection at a dose of 40 mg every other week, with the option of increasing the frequency of administration to once weekly. Higher dosages (80 mg) have not been shown to offer additional clinical benefits over the 40 mg dosage regimens. Like etanercept, it can be given alone or in combination with methotrexate. The combined use of adalimumab and methotrexate results in significantly better radiographic outcomes than when either agent is used alone. 8 Reactivation of latent tuberculosis has also been observed with adalimumab. Its half-life is the longest of the TNF-α inhibitors available, approximately 14 to 21 days.
Upward dose adjustment with infliximab has been reported in medical-scientific literature. An observational study conducted at McGill University Health Centre found that 26 of 41 patients (63%) continued treatment with infliximab beyond 22 weeks, and 15 of 26 patients (58%) who continued treatment experienced an upward dose adjustment either through increased use of Frequency, Predictors, and Economic Impact of Upward Dose Adjustment of Infliximab in Managed Care Patients With Rheumatoid Arthritis medication and/or reduction in the interval between infusions. 9 Similar findings were observed in retrospective analyses of patient medical records and detailed survey data (upward dose adjustment rates of 61% and 56%, respectively). 10 In addition, findings from a trial-based study of the serum concentrations of infliximab and clinical response indicate a high degree of correlation between these 2 measures. 11 The authors also cite anecdotal evidence from the study suggesting that up to one quarter of infliximab patients experience "breakthrough" joint pain and swelling several weeks prior to their next infliximab infusion, and recommend upward dose adjustment in these cases. Despite the frequency with which upward dose adjustments with infliximab appear to occur, conflicting data exist on the clinical benefits of these changes. The results of a case-control study comparing 44 Swedish RA patients with upward dose adjustment of infliximab to controls either not increasing infliximab dose (n = 44) or receiving etanercept (n = 36) suggest that improvements in disease activity among patients upwardly adjusting dose were no better than the best values prior to dose increase (e.g., best Disease Activity Score [DAS28] of 3.5 before versus 3.6 after dose increase) and did not differ materially in magnitude from improvements among controls. 12 In addition, findings from a cohort study of 68 patients with RA in Greece, in which more than three quarters of the sample required upward dose adjustment at some point over 12 infusions, indicate that response to treatment (as indicated by the European League Against Rheumatism response category) occurred in only 26% of those with upward dose titration. 13 The results of a medical record review of 244 RA patients treated with etanercept or infliximab over averages of 29 and 14 months, respectively, indicated that, while dosing for both medications was within label guidelines, the change in mean dosing from first to last administration was minimal among etanercept subjects (25.0 mg versus 25.8 mg respectively, P = 0.16), while dosing changes were significant among infliximab recipients (3.38 mg/kg versus 4.51 mg/kg, P <0.001). 14 In contrast to the above findings, the results of an observational study of 511 infliximab patients in Belgium suggest that loss of therapeutic response was overcome in the 112 patients (22%) who increased dose by at least 100 mg by week 30 of treatment 15 However, baseline disease activity scores were worse in the group that adjusted dose. The authors could not, therefore, rule out a "regression to the mean" effect in this analysis. It is also important to note that, while the labeling allows for consideration of dosing up to 10 mg/kg, the pivotal trials of infliximab did not evaluate clinical outcomes in patients who increased dosing over time; instead, patients were randomized to separate treatment groups based on initial dosing intensity (i.e., 3 mg/kg or 10 mg/kg) and schedule (every 8 or every 4 weeks). 6 The 2002 ACR guidelines do not specifically state when in the course of disease biological agents should be introduced in the treatment armamentarium of RA patients. 4 Initially, and not unlike how methotrexate was first used when approved by the FDA for RA in the late 1980s, these agents were first used in severe RA patients who had failed treatment with traditional DMARDs. Over time, all 3 TNF-α inhibitors have been shown to be effective in early RA (disease duration of 3 years or less), and an increasing percentage of patients with established RA are being treated with these drugs earlier in the course of their disease as familiarity with the agents grows. Because no controlled head-to-head clinical trials of these agents have been conducted to date, other considerations must be taken into account, such as dose and route of administration, use of concomitant therapies, expected half-life, and patient and/or physician preferences.
Consideration of the above variables cannot be made independently of concerns regarding health care costs, however. For this reason, variability in infliximab dosing regimens is likely to be of great interest to public and private third-party payers as drug acquisition costs alone may approach $11,000 annually in a patient dosed at the minimum level of 3 mg/kg, 16 and dosing changes appear to be more frequent and necessary with infliximab in comparison with the other available TNF-α inhibitors. This study used a large national administrative claims database to determine the frequency of upward dose adjustment with infliximab, the direct drug costs of infliximab, and the patient, provider, and health plan characteristics associated with dosing of infliximab.

Data Source
Data were obtained from the PharMetrics Patient-Centric Database, which, at the time of this evaluation, was composed of fully adjudicated (i.e., final paid claims, subsequent to reversals and adjustments) medical and pharmaceutical claims for more than 44 million unique patients from 75 health plans across the United States. The database includes both inpatient and outpatient diagnoses (in International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] format) and procedures (in ICD-9-CM, current procedural terminology , and Health Care Financing Administration Common Procedure Coding System [HCPCS] formats) as well as both community and mail-service pharmacy claims; available data on pharmacy claims include the National Drug Code (NDC) as well as days supplied and quantity dispensed (for a subgroup of datasets). Both paid and charged amounts are available for all services rendered as well as the date of service for all claims. Additional data elements include demographic variables (age, gender, geographic region), product type (i.e., health maintenance organization [HMO], preferred provider organization [PPO], point-of-service organization [POS], indemnity, other [e.g., hybrid plans]), payer type (i.e., commercial, Medicare Risk, managed Medicaid, self-insured employer), provider specialty, and start and stop dates for plan enrollment.
Records in the PharMetrics database are representative of the national commercially insured population on a variety of demographic measures, including geographic region, age, gender, and product type (e.g., HMO, PPO). The data are also longitudinal, with an average member enrollment time of 2 years. Only health plans submitting data for all of their members are included in the database. Data submissions are subjected to a series of data quality checks to ensure a standardized format and minimal error ratesfor example, presence of claim reversals or adjustments and errors in age and gender coding.

Sample Selection
All patients with a diagnosis of RA (ICD-9-CM 714.xx) who were newly started on infliximab (HCPCS code J1745, NDC code 57894003001) between June 1, 2000 (when infliximab received its HCPCS code), and June 30, 2002, were initially selected for the study. The date of the first prescription or infusion claim served as the patient' s "index" date. It is important to note that other evidence of infliximab use also may be available. Specifically, a small percentage of patients may have filled their prescriptions for infliximab at community pharmacies and taken their medication to their physician or clinic for infusion. To identify these patients, the following algorithm was considered to constitute an infliximab infusion: the presence of a prescription for infliximab, followed by a CPT-4 procedure code for an infusion within 7 days after the prescription. The sample was limited to patients with a minimum of 3 infliximab infusions because patients were assumed to have achieved their loading or "maintenance" dose (i.e., the dose arrived at after initial titration to an effective level) by the second infusion and were therefore not considered at risk of upward dose adjustment until the third infusion.
A 6-month pretreatment period was created in relation to the index date, the purpose of which was to collate baseline information for use in between-group comparisons as well as stratified and multivariate analyses; 6 months was chosen in order to maximize sample size because longer pretreatment durations would have reduced that sample and important strata to an untenable extent. All patients were followed for a minimum of 6 months after initiation of infliximab therapy; follow-up was allowed to vary beyond this minimum, however, in order to capture all available patient data. Follow-up was terminated as of the date of health plan disenrollment or end of available data, whichever came first. All relevant claims were then compiled for selected patients between December 1, 1999, and December 31, 2003.
Patients were excluded from the study sample if they (1) had a claim for infliximab or any other TNF-α inhibitor during the pretreatment period, (2) had a pretreatment and/or follow-up enrollment duration of less than 6 months, (3) were not continuously eligible for health and pharmacy benefits during the entire pretreatment and follow-up periods, and (4) were aged 65 years or older and their payer type was not Medicare "risk" (i.e., if the member was not enrolled in a health plan that agrees to assume financial risk for the full coverage of a Medicare beneficiary) since the accuracy of analyses of patients with gaps in coverage due to coordination of benefits between payers could not be validated.

Measures
Several selected demographic and clinical characteristics were measured among patients who did and did not receive upward dose adjustment of infliximab, including age, gender, plan type (i.e., HMO, PPO, POS, indemnity, other), geographic region (East, Midwest, South, West), physician specialty as of the index infusion (i.e., family practice/general practice, internal medicine, rheumatology, orthopedics/surgery, other), setting of infusion (i.e., clinic, office, pharmacy, patient' s home, other/unknown), the presence of selected pretreatment RA-related therapies (i.e., NSAIDs, COX-2 inhibitors, other miscellaneous anti-inflammatories, gold compounds, methotrexate, anakinra, leflunomide, other DMARDs, other RA-related therapy), the presence of selected pretreatment comorbidities (e.g., lupus, Crohn' s disease, depression, respiratory disorders), a longitudinal comorbidity index (i.e., Charlson with Deyo modification) 17 and selected pretreatment procedures (i.e., joint aspiration/injection procedures, synovectomy, arthroplasty, arthrodesis, arthroscopy, liver function tests, urinalysis, hematologic/serologic tests, bone/joint imaging, chest X-rays). In addition, total pretreatment RA-related and overall costs were calculated as a basic measure of population severity.
Upward dose adjustment was examined for those patients evaluable for such an analysis using 2 separate methods. First, the number of whole vials billed for infliximab was tallied (practitioners only bill for whole vials even though infliximab dosing is weight-based; while patients may therefore have partial vial use, this level of detail is not detectable in claims data). Second, the interval between infusions was assessed. Upward dose adjustment was defined as follows: (1) at least 1 occurrence per patient of the number of billed vials greater than the maintenance dose or (2) at least 2 occurrences of infusions with an interval of fewer than 49 days (this interval was selected to control for small discrepancies in the labeled infusion interval following the second infusion of 56 days [8 weeks] due to scheduling or other conflicts, while still allowing for consideration of a change to a 4-to 6-week interval as an upward dose adjustment).
The costs of RA-related medications and medical services were examined separately for patients who did and did not receive increased infliximab dose. Measures of interest included the use of RA-related medications as described above, outpatient care (i.e., physician office, emergency room, other), ancillary services (e.g., laboratory), and hospital admissions. Medical services were deemed to be RA-related based on the presence of an RA diagnosis (ICD-9-CM 714.xx) on the claim of interest.

Frequency, Predictors, and Economic Impact of Upward Dose Adjustment of Infliximab in Managed Care Patients With Rheumatoid Arthritis
Costs were tallied based on the amount paid by the health plan on relevant claims, net of any patient contribution (e.g., copayment, coinsurance); the perspective of these analyses was therefore that of the third-party payer. These costs are expressed in 2003 U.S. dollars and were adjusted as necessary using the medical care component of the U.S. Consumer Price Index (unpublished data, U.S. Bureau of Labor Statistics, 2004). In addition to RA-related costs, total non-RA-related costs (i.e., costs of medications other than those classified as RA-related above, and costs of outpatient and inpatient services without a listed diagnosis of RA) were also tallied. Because follow-up was variable beyond 6 months, costs were expressed on an annualized basis (i.e., standardized to a 365-day rate).

Analyses
Differences in patient characteristics were examined using chi-square tests for categorical variables and Wilcoxon ranksum tests for continuous variables. Differences in cost between the groups were assessed using Wilcoxon rank-sum tests. In addition, because the sample was self-selected, differences in patient characteristics would likely have confounded comparisons of costs between those who did and did not adjust their dose upward. Stratified cost analyses were therefore undertaken where the strata were defined based on characteristics found to differ significantly between the 2 cohorts of interest (Note: Multivariate modeling of the effects of upward dose adjustment on costs was not feasible because these variables were both tallied during the same time period).
Time from infliximab initiation to first upward dose adjustment was estimated using Kaplan-Meier techniques; separate probability function curves were created for patients initiating therapy in calendar years 2000, 2001, and 2002.
Multivariate determination of the factors independently and significantly associated with infliximab upward dose adjustment was estimated using a Cox proportional hazards model to control for right-censoring of data; results were expressed in terms of hazard ratios, along with corresponding 95% confidence intervals. Univariate findings as well as a priori determination of those factors likely to be clinically important predictors of upward dose adjustment were used to force selected variables into the initial model specification, including physician specialty, infusion setting, presence of pretreatment fibromyalgia, and pretreatment use of RA-related therapies. Other candidate variables were allowed to enter the model using stepwise selection (forward selection was tested and yielded identical results); those variables significant at P <0.10 were retained. All analyses were conducted using Statistical Analysis Software (SAS Institute, Cary, NC), version 8.2.

Upward Dose Adjustment and Patient Characteristics
A total of 1,388 patients were new to infliximab during the study timeframe and met all other study entry criteria (Table 1, Figure 1); a total of 1,236 had 3 or more infliximab infusions, and were therefore able to be evaluated for dose adjustment. Characteristics of this subset were essentially identical to those in the overall cohort of 1,388 patients; data not shown). A total of 762 patients in this subset (61.7%) experienced one or more upward dose adjustments during a mean of approximately 15 months of follow-up (Figure 1). Of the 61.7% of patients who experienced upward dose adjustment, the most common adjustment was an increase in the number of vials reported on the claim (63.3%); more than one quarter of patients experienced upward dose adjustment of both types (dose and frequency). Demographic and clinical characteristics of those who upwardly adjusted infliximab dose versus those who did not are presented in Table 2. Duration of follow-up ranged between 413 and 489 days on average for those upwardly adjusting and not adjusting dose respectively. The average age in both groups was approximately 50 years; three quarters of patients in both groups were female. Consistent with the general distribution of the PharMetrics database, the majority of patients were in the South and Midwest regions, and approximately 92% were enrolled in managed care (HMO, POS, or PPO) plans.

Study Sample by Reason for Attrition
The majority of patients received their initial infliximab infusion in a clinic setting. Pretreatment presence of methotrexate was significantly higher among infliximab dose-adjustment patients (64.4% versus 60.3%, P <0.001). The percentage of patients receiving methotrexate concurrently with infliximab in the follow-up period was somewhat lower than these figures in both groups but still significantly higher among dose-adjustment patients (62.2% versus 55.5%, P<0.001). Use of etanercept following infliximab initiation was minimal, occurring in fewer than 2% of patients in each group (7 and 9 patients for upward adjustment and no-adjustment patients, respectively).
The mean (SD) Charlson index was significantly higher among patients with increased infliximab dose (1.3 [0.9] versus 1.2 [0.8], P = 0.019), but the absolute difference is small and may not be clinically meaningful. Similarly, the mean pretreatment RA-related and total costs were significantly lower on average among these persons who experienced increased infliximab dose, but the absolute difference was small ($3,921 [$5,995] versus $4,065 [$10,991], respectively, P = 0.002), and perhaps not of practical significance. The mean maintenance infliximab dose also was slightly but significantly lower among patients with increased dose (2.54 [1.04] vials compared with 2.73 [1.17] vials for those infliximab patients without increased dose, P <0.001); the median maintenance dose was 2 vials for both groups.
Kaplan-Meier estimates of time to first upward dose adjustment are presented in Figure 2. Overall median time to upward adjustment was 254 days; time to adjustment declined steadily over time, however, from a high of 330 days among patients starting infliximab therapy in 2000 to 224 days for patients initiating infliximab therapy in 2002.

Predictive Model of Upward Dose Adjustment of Infliximab
The results of the Cox proportional hazards model of factors independently associated with upward dose adjustment are presented in Table 3. The single most important predictor of upward dose adjustment was pretreatment use of leflunomide, which was associated with a nearly 6-fold increase in the likelihood of upward dose adjustment (hazard ratio [HR] = 5.9670, 95% CI = 2.6230, 13.5740, P < 0.001). This is not entirely surprising since leflunomide is often used in patients with advanced disease who have previously failed methotrexate. The presence of comorbid Crohn' s disease was associated with a 40% lower likelihood of upward dose adjustment as was the receipt of infliximab on a community pharmacy basis. Interestingly, the initial infliximab dose was not a significant predictor of upward dose adjustment in these analyses.
There was a trend toward increased likelihood of upward dose adjustment among patients with comorbid scleroderma, fibromyalgia, and respiratory disorders, although none of these reached statistical significance. Additionally, there was a trend toward a protective effect from female gender, although this again did not reach statistical significance. Finally, the use of liver function tests during the pretreatment period was associated with a moderately increased likelihood of upward dose adjustment (HR = 1.1770; 95% CI = 1.0120, 1.3690; P = 0.035).

Infliximab Use and Costs of Medications and Health Care Services
Over a mean duration of follow-up of 16  Stratified total RA-related costs are presented in Table 5. Across nearly all strata, total costs remained significantly higher among patients who had their infliximab dose adjusted upward at a level of magnitude that was similar to overall comparisons. In all cases, total RA-related costs were higher for patients who had their infliximab dose adjusted upward.

II Discussion
In an effort to better understand the patterns of infliximab dosing in RA, factors predictive of upward dose adjustment, and the economic impact of this phenomenon in usual care (i.e., not a randomized controlled trial), a retrospective analysis of integrated medical and pharmacy claims data was undertaken. Our findings suggest that upward dose adjustment occurs in more than 60% of infliximab patients. In addition, it appears that upward dose adjustment is occurring earlier in the course of therapy, perhaps associated with emerging clinical data regarding breakthrough symptoms based on the original dosing schedule [9][10][11] ; the time to initial upward dose adjustment declined by 47% among those initiating therapy in calendar 2000 versus 2002 (medians of 330 and 224 days, respectively). Factors independently associated with infliximab upward dose adjustment included prior use of leflunomide, the presence of selected comorbidities, and prior receipt of liver function testing; prior use of leflunomide is likely associated with more advanced disease, as it is often used as a "last-resort" therapy prior to biologic initiation; similarly, liver function testing is likely a marker for prior methotrexate or leflunomide use, which require such monitoring.
Perhaps more importantly, patients who had their infliximab dose adjusted upward were more resource intensive and costlier to treat than those who did not upwardly adjust the dose. Total RA-related costs were higher by more than 50% among patients who received upward dose adjustment. While it might be expected that the increased costs of infliximab might be partially offset by reductions in outpatient, inpatient, or unrelated costs, the cost offset appears to be small. RA-related outpatient and inpatient costs were greater among patients who received upward dose adjustment of infliximab, and non-RA-related costs were only 2.4% lower ($7,816 versus $8,010, P = 0.03).
Based on our findings, in a typical 500,000-member managed care organization (MCO), one would expect that approximately 125 patients would receive infliximab for RA. Total costs of care (i.e., RA-related and unrelated) for these 125 patients, assuming no upward dose adjustment, would be approximately $2.8 million (i.e., 125 X $22,435). The cost of treating these patients in the 500,000-member MCO would be approximately $0.47 per member per month (PMPM). If upward dose adjustment occurred for only half of the 125 infliximab patients, total costs would increase by 17% or $0.008 PMPM to $3.3 million (62.5 X $22,435 + 62.5 X $30,099) or $0.55 PMPM.

Limitations
We note some important limitations of our analysis. Since this was a retrospective analysis of administrative claims data, results were based on amounts billed to health plans. As a result, the unit of measurement for infliximab is billed whole vials. For example, if 1.2 vials were administered to a patient, 2 vials would be billed to the health plan. Therefore, these results may, in fact, under-or overstate the precise rate of upward dose adjustment-for example, a patient who increases from 1.2 to 1.7 vials will be shown in the administrative claims to have utilized 2 vials in both instances; in contrast, a patient moving from a dose of 1.9 to 2.1 vials will appear to have been dosed upward from 2 to 3 vials. In addition, our findings indicate that only one half to two thirds of infliximab recipients received concomitant therapy with methotrexate; i.e., up to one half of patients did not receive infliximab in combination with methotrexate, contrary to FDA label instructions for combina-  tion use. Since we did not have access to medical charts, the reasons for this finding are not clear, and one should not assume that this represents off-label use of infliximab. This finding is similar to findings previously reported by Fitzcharles and colleagues, in which 46% of patients receiving infliximab did not have evidence of concomitant methotrexate therapy. 9 Use of medical records as a primary or validation of the administrative claims data was not possible for this analysis. Such data may have been useful for understanding key clinical characteristics in the subject populations, including time since disease onset, reasons for dosing changes, and other factors. A more precise estimate of dosing changes also may have been available using clinical data. It is important to note, however, that our findings regarding the rate of upward dose adjustment (62%) were remarkably similar to those obtained via record review or in clinical trial settings (56% to 61%). 9, 10 We do recognize, however, that the maintenance dose of infliximab was somewhat lower among those upwardly adjusting dose relative to those without such adjustment (2.54 versus 2.73 vials, respectively, P < 0.001)), indicating that some proportion of patients in the dose-adjustment group may, in fact, have been titrating to an effective initial maintenance dose.
The absence of information from medical charts also precluded determination of patient weight, the key variable in the dosing of infliximab. Patients in the upward dose adjustment group could have been, in aggregate, of higher average body weight than patients in the no-increase groups. Second, since infliximab dosing levels may range from 3 mg/kg to 10 mg/kg, dosing changes can result from weight changes alone.
Also, one method of estimation of dose change for infliximab was based on 2 or more instances of infliximab being administered during an interval < 49 days (7 weeks), which is only 1 week in variance to the recommendation for dosing every 8 weeks. It is possible that some patients may have had these nonstandard dosing intervals simply as a result of scheduling availability and not as a result of upward dose adjustment. The sensitivity of our findings to use of a different threshold (e.g., 42 days) is unknown; in addition, we did not examine the pattern in dosing intervals for revealing trends, such as a 7-week interval followed by two 8-week intervals, followed by  We also note that, due to the limitations of the data source used, it was not possible to examine the impact of upward dose adjustment on key clinical and humanistic outcomes of interest in a population with RA, including patient function, health-related quality of life, radiographic progression of disease, and other critical end points. Our findings did show that increased costs of care were essentially driven almost entirely by differences in health plan costs for infliximab, indicating that any clinical benefit derived from upward dose adjustment did not translate into economic benefit during the period of observation, except for the small but statistically significant lower non-RA-related cost (annualized $194 or 2.4%) in the upward dose adjustment group.
Finally, as with all studies of administrative claims, we cannot rule out the possibility that differences in disease progression and/or severity (i.e., selection bias) between patients who did and did not receive an increase in infliximab dose may have influenced our findings; for example, patients in the dose-increase group may have incurred higher costs in part because of a more complex medical condition than those in the no-increase group. Nevertheless, our results remained statistically significant even after stratifying on observed differences between groups; in addition, cost differences were attributed almost entirely to differences in the amount of use and cost of infliximab itself. We, therefore, believe that any selection bias would likely only affect the magnitude, and not the direction, of our findings.

II Conclusions
Despite these limitations, our study has some implications for payers, patients, and providers. Upward dose adjustment is a common phenomenon among patients with RA who receive infliximab therapy and appears to now be occurring earlier in the course of therapy. Upward dose adjustment is also associated with an increase of more than 50% in medication costs. While medical chart information was not available for this study, any clinical benefits derived from upward dose adjustment did not appear to translate into cost savings in our study, except for the small but statistically significant lower non-RA-related cost in the upward dose adjustment group. Dosing trends are therefore relevant when estimating the economic impact of TNF-α inhibitor therapy among patients with RA.

DISCLOSURES
This study was funded by an unrestricted grant to PharMetrics, Inc., from Bristol-Myers Squibb (BMS) Company. BMS is currently developing medications to treat rheumatoid arthritis and other autoimmune diseases. PharMetrics has ongoing consulting and research relationships with BMS and numerous other pharmaceutical and biotech companies. Author Daniel A. Ollendorf is employed by PharMetrics, and author Somali Misra Burgess was employed by PharMetrics at the time of this study. Authors Elena Massarotti and Charles Birbara received honoraria from PharMetrics for their participation in this study and also have ongoing consulting relationships with BMS.
Ollendorf served as principal author of the study. Study concept and design were contributed by Ollendorf, Massarotti, Birbara, and Burgess. Analysis and interpretation of data were contributed by Ollendorf and Burgess. Drafting of the manuscript was primarily the work of Ollendorf and Burgess, and its critical revision was the work of all authors. Statistical expertise and administrative, technical, and/or material support was provided by Ollendorf.